ABSTRACT
Excessive and inappropriate action of transforming growth factor (TGF)-beta has been implicated in the pathogenesis of several disease processes, especially cancer and fibrosis. To identify antagonists of the TGF- beta ligand-binding domain that may have therapeutic potential, we screened the National Cancer Institute open access chemical repository for molecules that inhibited binding of TGF-beta to the type II receptor (TbetaRII). About 30,000 molecules were screened resulting in the identification of five structurally related molecules that reduced binding of TGF-beta1 to soluble TbetaRII with an ED50 of approx 10 microM. The chemicals blocked inhibition of Mv1Lu cell growth by TGF-beta, TGF-beta - induced expression of luciferase driven by the TGF-beta response element, and induction of plasminogen inhibitor mRNA detected by Northern blot. In contrast, the chemicals did not block activin-induced inhibition of cell growth. Our results identify a novel chemical group that blocks binding of TGF-beta to its receptor and may result in novel treatment for disease.
Subject(s)
Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1/antagonists & inhibitors , Transforming Growth Factor beta1/metabolism , Activins/metabolism , Animals , Blotting, Northern , CHO Cells , Cell Line, Tumor , Cricetinae , Cricetulus , Drug Evaluation, Preclinical , Gene Expression/drug effects , Humans , Protein Binding/drug effects , Receptors, Transforming Growth Factor beta/isolation & purification , Transforming Growth Factor beta1/isolation & purificationABSTRACT
Considerable evidence demonstrates that genetic factors are important in the development and aggressiveness of prostate cancer. To identify genetic variants that predispose to prostate cancer we tested candidate SNPs from genomic regions that show linkage to prostate cancer susceptibility and/or aggressiveness, as well as genes that show a significant difference in mRNA expression level between tumor and normal tissue. Cases had histologically verified prostate cancer. Controls were at least 65 years old, never registered a PSA above 2.5 ng/ml, always had digital rectal examinations that were not suspicious for cancer, and have no known family history of prostate cancer. Thirty-nine coding SNPs and nine non-coding SNPs were tested in up to 590 cases and 556 controls resulting in over 40,000 SNP genotypes. Significant differences in allele frequencies between cases and controls were observed for ID3 (inhibitor of DNA binding), p = 0.05, HPN (hepsin), p = 0.009, BCAS1 (breast carcinoma amplified sequence 1), p = 0.007, CAV2 (caveolin 2), p = 0.007, EMP3 (epithelial membrane protein 3), p < 0.0001, and MLH1 (mutL homolog 1), p < 0.0001. SNPs in three of these genes (BCAS1, EMP3 and MLH1) remained significant in an age-matched subsample.
Subject(s)
Genetic Predisposition to Disease , Prostatic Neoplasms/genetics , Gene Frequency , Genotype , Humans , Likelihood Functions , Male , Neoplasm Invasiveness/genetics , Polymorphism, Single NucleotideABSTRACT
Prostate cancer is the most frequently diagnosed visceral cancer of men, responsible for approximately 40,000 deaths in adult males per year. To identify the genetic causes of prostate cancer, we performed a whole genome scan of affected sib pairs, using DNA markers spaced evenly across the human genome. We demonstrated that regions on chromosomes 1, 4, 5, 7, 8, 11, 16 and 19 might harbor genes that predispose individuals to prostate cancer and may affect tumor growth rate and tumor aggressiveness. Here we present DNA sequence analysis of KIAA 0872 and 17-beta hydroxysteroid dehydrogenase that are located on chromosome 16 within the mapped region, and we demonstrate that neither of these genes carries mutations in the protein coding region or their splice junction sites. These results suggest that these genes are less likely to be associated with the cause of familial prostate cancer.
Subject(s)
Chromosome Mapping , Chromosomes, Human, Pair 16 , Genetic Testing , Prostatic Neoplasms/genetics , 17-Hydroxysteroid Dehydrogenases/genetics , Adult , Aged , Alternative Splicing/genetics , Cell Line, Tumor , Genomics , Humans , Male , Middle Aged , Polymorphism, GeneticABSTRACT
BACKGROUND: Nasal polyps are considered to result from chronic inflammation, but the initial or persisting stimulus for the inflammation is not known. A variety of bacteria and fungi have been cultured from nasal polyps, but approximately 35% have sterile cultures. Previously, Mycoplasma pneumoniae-specific DNA was detected in human nasal polyps using polymerase chain reaction (PCR) techniques, suggesting M. pneumoniae as a causative agent in the etiology of nasal polyps. METHODS: In this study, we tested for the presence of bacterial DNA in nasal polyps resected from 40 patients, in nasal mucosa membrane from 9 patients undergoing turbinectomy for hypertrophy, and in sinus mucosa membrane from 6 patients undergoing endoscopic surgery for chronic sinusitis. Tissue DNA was extracted and analyzed by PCR using M. pneumoniae specific primers for DNA that encode the 16S rRNA gene in 41 specimens (31 polyps, 6 turbinates, and 4 sinus), and by consensus sequence-based PCR using broad range primers for most eubacterial DNA encoding the 16S rRNA gene in 38 specimens (26 polyps, 7 turbinates, and 5 sinuses). RESULTS: Only two samples were positive for bacterial DNA encoding 16S rRNA: Streptococcus sp. DNA was isolatedfrom one polyp specimen and Pseudomonas aeruginosa DNA was isolated in one maxillary sinusitis specimen. No evidence of M. pneumoniae-specific DNA encoding 16S rRNA was found in any of the tissues. CONCLUSIONS: This study suggests that chronic bacterial infection is not a major component of nasal polyp etiology.
